Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

The role of subcutaneous adipose tissue in psoriasis.

It is widely accepted that obesity is a systemic comorbidity factor in psoriasis. At the same time, there is rapidly growing evidence that the adipose tissue is not only systemically but also locally involved in the pathophysiology of psoriasis and in response to successful anti-psoriatic treatment.

DERMAL ADIPOSE TISSUE IN HAIR FOLLICLE CYCLING: POSSIBLE APPLICATIONS IN ALOPECIA?

Cross-talk between the hair follicles (HFs) in different stages of their cycling and adjacent adipose tissue is a new important topic which is of both theoretical and practical interest. Objective - to analyze available data on possible interrelationship of dermal adipose tissue and hair follicle cycling. Experimental results obtained in rodents clearly demonstrate that HFs cycling is connected to adjacent dermal adipose tissue. Recently uncovered adipocyte-myofibroblast transition can be significantly involved in miniaturization of HFs and be an important pathophysiological step in androgenetic alopecia. Improvement of adipogenic environment of HFs can be important both in treatment of alopecia and in surgical hair restoration procedures.

[Very high frequency ultrasound: New therapeutic method in aesthetic medicine and dermatology]. / Sehr hochfrequenter Ultraschall : Neues Therapieverfahren in der Ästhetik und Dermatologie.

Very high frequency ultrasound (VHF-US) is new therapy method with a broad application spectrum in dermatology and aesthetic medicine. In this method, ultrasound waves with frequencies over 10 MHz, which were for a long time only used in ultrasound diagnostics, are applied for therapeutic purposes. Such US waves demonstrate specific biophysical efficiencies which warrant their application for the treatment of the skin efflorescences, chronic wounds and hypertrophic scars as well as in anti-aging and skin improvement procedures in aesthetic medicine. VHF-US can be applied not only for stand-alone treatments, but also as a supportive pre- and posttreatment method in combination with laser, radiofrequency currents, injection lipolysis, etc. as well as in aesthetic plastic surgery.

Description of radiation- and ultrasound-induced cell death by a stochastic process.

Cell survival is a stochastic process with the stochastic component being strongly dependent on the irradiation conditions. This process is described by a stochastic model which allows differentiation between the deterministic and stochastic components of survival. The proposed model is tested for four irradiation experiments (2 with ionizing radiation and 2 with ultrasound) and very good agreement with experimental results is demonstrated. It identifies the higher stochasticity of the cell survival for the temporally varying radiation fields and provides the possibility to compare the stochasticity of survival in different radiation fields.

Changes in functioning of rat submandibular salivary gland under streptozotocin-induced diabetes are associated with alterations of Ca2+ signaling and Ca2+ transporting pumps.

Xerostomia and pathological thirst are troublesome complications of diabetes mellitus associated with impaired functioning of salivary glands; however, their cellular mechanisms are not yet determined. Isolated acinar cells were loaded with Ca2+ indicators fura-2/AM for measuring cytosolic Ca2+ concentration ([Ca2+]i) or mag-fura-2/AM-inside the endoplasmic reticulum (ER). We found a dramatic decrease in pilocarpine-stimulated saliva flow, protein content and amylase activity in rats after 6 weeks of diabetes vs. healthy animals. This was accompanied with rise in resting [Ca2+]i and increased potency of acetylcholine (ACh) and carbachol (CCh) but not norepinephrine (NE) to induce [Ca2+]i transients in acinar cells from diabetic animals. However, [Ca2+]i transients mediated by Ca2+ release from ER stores (induced by application of either ACh, CCh, NE, or ionomycin in Ca2+-free extracellular medium) were decreased under diabetes. Application of inositol-1,4,5-trisphosphate led to smaller Ca2+ release from ER under the diabetes. Both plasmalemma and ER Ca2+-ATPases activity was reduced and the latter showed the increased affinity to ATP under the diabetes. We conclude that the diabetes caused impairment of salivary cells functions that, on the cellular level, associates with Ca2+ overload, increased Ca2+-mobilizing ability of muscarinic but not adrenergic receptors, decreased Ca2+-ATPases activity and ER Ca2+ content.

Effect of streptozotocin-induced diabetes on the activity of calcium channels in rat dorsal horn neurons.

We have previously found that spinal dorsal horn neurons from streptozotocin-diabetic rats, an animal model for diabetes mellitus, show the prominent changes in the mechanisms responsible for [Ca2+]i regulation. The present study aimed to further characterize the effects of streptozotocin-induced diabetes on neuronal calcium homeostasis. The cytoplasmic Ca2+ concentration ([Ca2+]i) was measured in Fura-2AM-loaded dorsal horn neurons from acutely isolated spinal cord slices using fluorescence technique. We studied Ca2+ entry through plasmalemmal Ca2+ channels during potassium (50 mM KCl)-induced depolarization. The K+-induced [Ca2+]i elevation was inhibited to a different extent by nickel ions, nifedipine and omega-conotoxin suggesting the co-expression of different subtypes of plasmalemmal voltage-gated Ca2+ channels. The suppression of [Ca2+]i transients by Ni2+ (50 microM) was the same in control and diabetic neurons. On the other hand, inhibition of [Ca2+]i transients by nifedipine (50 microM) and omega-conotoxin (1 microM) was much greater in diabetic neurons compared with normal animals. These data suggest that under diabetic conditions the activity of N- and L- but not T-type voltage-gated Ca2+ channels substantially increased in dorsal horn neurons.

Changes in calcium signalling in dorsal horn neurons in rats with streptozotocin-induced diabetes.

Intracellular calcium signalling was studied in the dorsal horn from neurons of rats with streptozotocin-induced diabetes versus control animals. The cytoplasmic Ca2+ concentration ([Ca2+]i) was measured in Fura-2 acetoxymethyl ester-loaded dorsal horn neurons from acutely isolated spinal cord slices using a fluorescence technique. The recovery of depolarization-induced [Ca2+]i increase was delayed in diabetic neurons compared with normal animals. In normal neurons, [Ca2+]i after the end of KCl depolarization recovered to the basal level monoexponentially with a time constant of 8.0+/-0.5 s (n = 23), while diabetic neurons showed two exponentials in the [Ca2+]i recovery. The time constants of these exponentials were 7.2+/-0.5 and 23.0+/-0.6 s (n = 19), respectively. The amplitude of calcium release from caffeine-sensitive endoplasmic reticulum calcium stores became significantly smaller in diabetic neurons. The amplitudes of [Ca2+]i transients evoked by 30 mM caffeine were 268+/-29 nM (n = 13) and 31+/-9 nM (n = 17) in control and diabetic neurons, respectively. We conclude that streptozotocin-induced diabetes is associated with prominent changes in the mechanisms responsible for [Ca2+]i regulation, which presumably include a slowdown of Ca2+ elimination from the cytoplasm by the endoplasmic reticulum.

Description of radiation-induced cell death by a stochastic differential equation.

An attempt to describe the dose dependence of cell inactivation by a stochastic differential equation is made. For this, a stochastic variable in dose radiosensitivity is introduced. Some solutions of the stochastic equation are obtained and and analyzed. How to obtain the value of the noise intensity of radiosensitivity from the experimental data is shown. Comparison of the theory with experimental data gives good results.

Modeling of the stochastic dynamics of radiation cell death: general approaches and some applications.

A description of the stochastic dynamics of radiation cell death based on the first-passage model is given. Both quasistochastic and stochastic methods of description are considered. Distributions of the time to cell death for stable and unstable populations are obtained. These results are used to analyze the dynamics of interphase death of thymocytes and bone marrow cells.

Dose-effect relations for stochastic rates of injury formation in cells.

The dose dependencies of lesion formation and cell survival are obtained for the imparting energy stochastic in time. It is shown that for the second-order dependence of the number of lesions on the radiation field one obtains the linear-quadratic dose dependence in the high dose range. The appearance of the linear component is related to the fluctuations and correlations of the rate of imparted energy. Expressions are obtained for cell survival in the one-target model for pulsed and prolonged irradiations.

Hit rates and radiation doses to nuclei of bone lining cells from alpha-particle-emitting radionuclides.

Factors relating the local concentration of a bone-seeking alpha-particle emitter to the mean hit rate have been determined for nuclei of bone lining cells using a Monte Carlo procedure. Cell nuclei were approximated by oblate spheroids with dimensions and location taken from a previous histomorphometric study. The Monte Carlo simulation is applicable for planar and diffuse labels at plane or cylindrical bone surfaces. Additionally, the mean nuclear dose per hit, the dose mean per hit, the mean track segment length and its second moment, the percentage of stoppers, and the frequency distribution of the dose have been determined. Some basic features of the hit statistics for bone lining cells have been outlined, and the consequences of existing standards of radiation protection with regard to the hit frequency to cell nuclei are discussed.

Metabotropic purinoreceptors in rat dorsal horn neurones: predominant dendritic location.

Elevations of cytosolic free Ca2+ concentration ([Ca2+]i) induced by addition of ATP have been compared in rat dorsal horn neurones in slices and after their isolation. ATP application induced in neurones in situ a rise of [Ca2+]i by 201 +/- 12 nM. In Ca2+-free external solution the rise was 156 +/- 14 nM (n = 45 of 76), indicating the presence of active purinergic metabotropic receptors in about 59% of neurones. [Ca2+]i transients induced by 2MeSATP in Ca2+-free external solution were completely abolished by 10 microM PPADS, indicating that some of the corresponding receptors are of the P2Y1 type. In acutely isolated neurones which lost their dendrites, there were no metabotropic response. The results confirm the presence of metabotropic postsynaptic purinoreceptors located in the dendritic tree of dorsal horn neurones.

[Diffusion model of coordinated oxygen and glucose uptake by solid tumor cells]. / Diffuzionnaia model' soglasovannogo pogloshcheniia kisloroda i gliukozy kletkami solidnoi opukholi.

A model for consistent oxygen and glucose uptake by tumor cells is suggested. Oxygen uptake is considered to depend, under certain conditions, on that of glucose. Equations for calculation of oxygen and glucose distributions in cell spheroids are given (models of solid tumor in vitro).

The effect of nimodipine on calcium homeostasis and pain sensitivity in diabetic rats.

1. The pathogenesis of diabetic neuropathy is a complex phenomenon, the mechanisms of which are not fully understood. Our previous studies have shown that the intracellular calcium signaling is impaired in primary and secondary nociceptive neurons in rats with streptozotocin (STZ)-induced diabetes. Here, we investigated the effect of prolonged treatment with the L-type calcium channel blocker nimodipine on diabetes-induced changes in neuronal calcium signaling and pain sensitivity. 2. Diabetes was induced in young rats (21 p.d.) by a streptozotocin injection. After 3 weeks of diabetes development, the rats were treated with nimodipine for another 3 weeks. The effect of nimodipine treatment on calcium homeostasis in nociceptive dorsal root ganglion neurons (DRG) and substantia gelatinosa (SG) neurons of the spinal cord slices was examined with fluorescent imaging technique. 3. Nimodipine treatment was not able to normalize elevated resting intracellular calcium ([Ca(2+)]( i )) levels in small DRG neurons. However, it was able to restore impaired Ca(2+) release from the ER, induced by either activation of ryanodine receptors or by receptor-independent mechanism in both DRG and SG neurons. 4. The beneficiary effects of nimodipine treatment on [Ca(2+)]( i ) signaling were paralleled with the reversal of diabetes-induced thermal hypoalgesia and normalization of the acute phase of the response to formalin injection. Nimodipine treatment was also able to shorten the duration of the tonic phase of formalin response to the control values. 5. To separate vasodilating effect of nimodipine Biessels et al., (Brain Res. 1035:86-93) from its effect on neuronal Ca(2+) channels, a group of STZ-diabetic rats was treated with vasodilator - enalapril. Enalapril treatment also have some beneficial effect on normalizing Ca(2+) release from the ER, however, it was far less explicit than the normalizing effect of nimodipine. Effect of enalapril treatment on nociceptive behavioral responses was also much less pronounced. It partially reversed diabetes-induced thermal hypoalgesia, but did not change the characteristics of the response to formalin injection. 6. The results of this study suggest that chronic nimodipine treatment may be effective in restoring diabetes-impaired neuronal calcium homeostasis as well as reduction of diabetes-induced thermal hypoalgesia and noxious stimuli responses. The nimodipine effect is mediated through a direct neuronal action combined with some vascular mechanism.

[One variational task of microdosimetry]. / Ob odnoi variatsionnoi zadache mikrodozimetrii.

A basic task of dosimetry, that is, the determination of the frequency distribution of specific energy as a function of radiation dose, has been formulated variationally. The optimal, by entropy, distribution has been found. The obtained ratios are used in describing the radiobiological effects with satiation.

[Generalization of microdosimetric correlations for the non-Poisson random process]. / Obobshchenie nekotorykh mikrodozimetricheskikh sootnoshenii na sluchai nepuassonovskogo sluchainogo protsessa.

The relationship between a radiation dose and moments of density of sensitive microvolumes distribution by the value of the absorbed specific energy was found for a random non-Poisson's distribution of the number of particle passages through a cell microvolume. A deviation from the Poisson's distribution was shown to cause a substantial modification of the microdosimetric results.

[Dose-effect curves in stochastic radiation intensity]. / Krivye doza--éffekt pri stokhasticheskoi intensivnosti izlucheniia.

Dose-response curves of the lesions yield and cell survival rate are obtained for radiation intensity stochastic in time. It was shown that, by analogy with the microdosimetric description, the quadratic dependence, that presents the lesions yield as a function of radiation intensity within the high dose range, is to produce a linear-quadratic dose response. The appearance of a linear component is conditioned by the correlativity of radiation. The asymptotic values are obtained for a single-hit scheme survival rate in the cases of prolonged and pulse irradiation.